Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson's disease.

BACKGROUND: Cannabis can alleviate pain of various etiologies. This study assessed the effect of cannabis on motor symptoms and pain parameters in patients with Parkinson's disease (PD). METHODS: Twenty patients with PD who were licensed to use cannabis underwent evaluation before and 30 min after cannabis consumption and again after long-term use. Motor function was assessed with the Unified PD Rating scale (UPDRS) by two raters, one blinded. Pain was assessed with the Pain Rating Index (PRI) and Visual Analogue Scale (VAS) of the short-form McGill Pain Questionnaire. Thermal quantitative sensory testing (QST) was performed in 18 patients. The two consecutive QST measurements were validated in 12 cannabis-naïve patients with PD. RESULTS: There was a significant decrease from baseline to 30 min after cannabis consumption in mean motor UPDRS score (38.1 ± 18 to 30.4 ± 15.6, p < 0.0001), total PRI (27 ± 13.5 to 9.7 ± 11, p = 0.001), and VAS score (6.4 ± 2.8 to 3.6 ± 3.1, p = 0.0005). Mean cold pain threshold decreased significantly in the more affected limb, but only after exclusion of two patients who consumed cannabis by vaporizer rather than smoking (19.5 ± 5.2 to 15.6 ± 8.7 °C, p = 0.02). After long-term (median 14 weeks) exposure, mean heat pain threshold decreased significantly in the more affected limb in all treated patients (43.6 ± 3.5 to 40.9 ± 3.3 °C, p = 0.05) and in cannabis smokers (43.7 ± 3.6 to 40.3 ± 2.5 °C, p = 0.008). CONCLUSIONS: Cannabis improved motor scores and pain symptoms in PD patients, together with a dissociate effect on heat and cold pain thresholds. Peripheral and central pathways are probably modulated by cannabis. SIGNIFICANCE: Quantitative sensory test results are significantly altered following cannabis consumption in patients with PD. Cannabis probably acts on pain in PD via peripheral and central pathways.

Contribution of genetic variants to pain susceptibility in Parkinson disease.

BACKGROUND: Pain is a one of the most disturbing non-motor symptoms of Parkinson disease (PD). The susceptibility to pain varies substantially among patients with PD. The aim of this study was to assess a potential association of genetic variants to PD-related pain. METHODS: We analysed 20 candidate SNPs from 12 genes previously reported to be associated with various pain phenotypes in a homogeneous group of 229 Israeli Jewish PD patients, with and without pain (n = 165 and 64, respectively). RESULTS: The statistical analysis accounted for the potential influence of demographic and clinical factors. The non-synonymous rs6746030 single nucleotide polymorphism (SNP) of the SCN9A gene, which alters the coding sequence of the sodium channel Nav1.7 (arginine to tryptophan), was nominally associated with PD-related pain susceptibility (p = 0.037), as well as with central and musculoskeletal pain subtypes independently. The synonymous rs324419 SNP of the FAAH gene which encodes fatty acid amide hydrolase, a cannabinoid metabolizing enzyme, was associated with PD-related pain (p = 0.006) and specifically with the musculoskeletal subtype. The FAAH haplotype of rs324419 and rs2295633 SNPs, which was previously associated with the variability in pain response in humans, was also associated with PD-related pain (p = 0.012) and specifically with PD-related musculoskeletal pain. CONCLUSIONS: Variants within in the SCN9A and FAAH genes were associated with the risk of pain in PD patients. These findings may contribute to our understanding of pain mechanisms of PD and to direct future therapies.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers.

OBJECTIVE: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. METHODS: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. RESULTS: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). CONCLUSIONS: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease.

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.

High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Whole genome analysis in a consanguineous family with early onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.

Clinical characteristics of Parkinson's disease among Jewish Ethnic groups in Israel.

Yemenite Jews in Israel are a distinctive ethnic division of the Jewish diaspora. Clinical findings, disease course and genetic tests for the LRRK2 6055G > A (G2019S) mutation were compared between Ashkenazi and Yemenite Israeli patients with Parkinson's disease (PD). Age of onset was significantly younger in the Yemenites (P < 0.001). There were no differences in the distribution of initial symptoms, environmental risk factors or rate of motor/non-motor phenomena. The Yemenite group had a more severe disease (P < 0.001), and a more rapid disease course (P = 0.006). The frequency of Lrrk2 substitution was 12.7% in the Ashkenazi group and was not observed in the Yemenites. These results show that there are differences between Israeli Jewish ethnic groups in the severity and progression of PD, but not in clinical symptoms. The high frequency of Lrrk2 G2019S in the Ashkenazi and its absence in the Yemenite Jews suggests a specific ancestral pattern of inheritance in Ashkenazi Jews.

[(123)I]-FP-CIT SPECT and olfaction test in patients with combined postural and rest tremor.

Mixed-type tremors pose a clinical diagnostic challenge. The aim of the study was to better characterize patients with combined postural and rest tremor. Patients were categorized into four groups: essential tremor (ET) (n = 7), combined rest + postural tremor (n = 17), PD (n = 17), and control subjects (n = 9). All underwent the University of Pennsylvania Smell Identification Test (UPSIT). The mixed-tremor group was also evaluated with SPECT imaging using the dopamine transporter (DaT) ligand (123)I-labeled FP-CIT. There was no significant difference in olfaction scores between the mixed tremor and essential tremor groups (23.2 +/- 6.6 vs 21.7 +/- 4.9) or between these groups and controls (27.2 +/- 5.0). The patients with PD had significantly lower scores than all the other groups (13.7 +/- 5.4, p < 0.001). Of the 12 patients with mixed tremor evaluated by SPECT, 9 had normal findings. This study suggests that rest tremor is part of the spectrum of ET, even in patients with long-standing disease. However, in a minority of patients, there might be transformation of ET-PD.

Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment.

To assess severity and progression of self-perceived dysautonomia and their impact on health-related quality of life (Hr-QoL) in multiple system atrophy (MSA), twenty-seven patients were recruited by the European MSA Study Group (EMSA-SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36), and they were assessed using the 3-point global disease severity scale (SS-3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow-up, the self completed COMPASS Change Scale (CCS), the SF-36, SS-3, and UMSARS were obtained. MSA patients showed marked self-perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow-up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF-36 scores. Progression of self-perceived dysautonomia did not correlate with global disease progression. Hr-QoL scores were stable during follow-up. This is the first study to investigate self-perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.

Skin biopsy for assessment of autonomic denervation in Parkinson's disease.

Autonomic dysfunction in Parkinson's disease (PD) is considered a late complication of the disease or an adverse effect of anti-parkinsonian medications. Morphological changes are demonstrated only by postmortem examination. The study objective was to evaluate peripheral autonomic neural involvement in PD using punch skin biopsy. The study sample included 22 patients (mean age 50 +/- 7.7 years, mean disease duration 5.3 +/- 3.8 years) and 19 controls. Four-millimeter skin biopsies were immunohistochemically stained with anti-PGP 9.5 antibody. Autonomic innervation of the blood vessels, sweat glands, and erector pili muscles was assessed and rated from 0 (normal) to 2 (severe). Cutaneous autonomic innervation was decreased in patients compared to controls. Semi quantitative analysis demonstrated reduced autonomic innervation of the blood vessels (1.0 +/- 0.8 vs. 0.42 +/- 0.8 in controls; p < 0.02), of sweat glands (0.95 +/- 0.67 vs. 0.47 +/- 0.61; p < 0.02) and of the erector pili muscles (1.06 +/- 0.55 vs 0.21 +/- 0.42; p < 0.001). This method demonstrates that the peripheral autonomic system is affected in PD at early stage of the disease and that autonomic involvement in PD may be more prevalent than previously thought.

Primary postural instability: a cause of recurrent sudden falls in the elderly.

Elderly patients with recurrent falls are frequently diagnosed with an extrapyramidal syndrome. This study aims to characterise a distinct group of patients with recurrent falls and postural instability as a hallmark of the clinical examination. The study took place in the Movement Disorders Unit, Rabin Medical Center, Petah Tiqva, Israel among 26 patients with recurrent falls who had no clinical evidence of a neurodegenerative disease. Medical records, neurological examination and brain imaging studies were assessed. Falls in these patients were sudden, unprovoked, with no vertigo or loss of consciousness. All had postural instability with minimal or no abnormality on the neurological examination. Brain imaging showed diffuse ischaemic changes in 65%. [(123)I]-FPCIT SPECT with the dopamine transporter ligand, performed in five patients, was normal in all. Recurrent falls might be caused by a neurological syndrome that primarily affects balance control. The importance of identifying this disorder is its distinction from other parkinsonian syndromes causing falls.

The European Multiple System Atrophy-Study Group (EMSA-SG).

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder for which no restorative or neuroprotective therapy is available. Interest has recently been directed to association studies on polymorphisms of various genes, mainly those related to dopamine metabolism and transport, and their effect on response to PD, which includes primarily levodopa and dopaminomimetics. Approximately 15-20% of patients with PD do not respond to levodopa, and the majority of those who do respond develop adverse fluctuations in motor response, primarily levodopa-induced dyskinesias. This review summarizes the influence of polymorphisms in various genes on the relative risk of IPD and on levodopa efficacy. It focuses on the importance of well-designed polymorphism studies that include large samples of patients with IPD and tightly matched controls and use identical methodologies. Valid data on such polymorphisms might increase the efficacy of levodopa, decrease its side effects, and reduce the occurrence of levodopa-induced dyskinesias. They might also provide a novel diagnostic tool for PD.

Quantitative measurement of pain sensation in patients with Parkinson disease.

BACKGROUND: Pain is common in patients with Parkinson disease (PD) and can precede the diagnosis of the disease. Experimental studies and clinical evidence indicate involvement of basal ganglia and dopaminergic pathways in central pain processing. OBJECTIVE: To quantitatively assess and compare pain perception in patients with unilateral PD with and without pain and in patients with response fluctuations. METHODS: Thirty-six patients with PD (mean age, 61.8 +/- 11.2 years) with predominantly unilateral disease, 15 patients with response fluctuations (mean age, 65.3 +/- 10.4 years), and 28 age-matched healthy control subjects participated in the study. Subjective pain was assessed using the visual analog scale with von Frey filaments for tactile thresholds and contact thermode for warm sensation (WS) and heat pain thresholds (HPTs). RESULTS: Tactile and WS thresholds did not differ between patients in both patient groups and control subjects nor between sides. HPT was lower in patients with PD who experienced pain (n = 21) compared with those who did not (42.6 +/- 3.0 degrees C vs 45.6 +/- 2.8 degrees C; p < 0.01) and those who experienced pain in the more affected side (41.4 +/- 2.6 degrees C vs 43.7 +/- 3.3 degrees C; p < 0.0001). In patients with fluctuations there were no side differences in WS and HPT or between "on" and "off" periods. CONCLUSION: Endogenous pain in patients with Parkinson disease is accompanied by increased sensitivity to some painful stimuli, suggesting that basal ganglia abnormality also involves pain encoding.

Familial infantile bilateral striatal necrosis: clinical features and response to biotin treatment.

BACKGROUND: Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric, spongy degeneration of the caudate nucleus, putamen, and globus pallidus. The familial form of IBSN is rare, and inheritance is either autosomal recessive or maternal. METHOD: The authors describe an Israeli Bedouin kindred in which 15 children born to consanguineous parents were affected with familial IBSN. They evaluated the clinical and radiologic evolution of the disease in 11 patients and the cerebral pathologic findings in one patient. Three of the children were treated with oral biotin 100 mg/day. RESULTS: Inheritance was apparently autosomal recessive. The untreated children had a similar clinical picture including developmental arrest beginning at the age of 7 to 15 months, choreoathetosis, and dysphagia. Pendular nystagmus appeared at a late stage. MRI, performed at various stages of the disease, showed severe basal ganglia atrophy. Postmortem study in one patient showed severe atrophy of the lenticular nuclei with gliosis and loss of neurons. Biotin, 100 mg/day, administered to the proband over a period of 15 months, may have slowed progression. In two other children treatment was initiated earlier and appeared to arrest or improve disease. CONCLUSIONS: Familial infantile bilateral striatal necrosis was inherited as an autosomal recessive trait. Clinical features included developmental arrest, dysphagia, and choreoathetosis. Imaging and pathology showed atrophy and degeneration of the basal ganglia. Oral biotin may have benefited three children.

The effect of deprenyl washout in patients with long-standing Parkinson's disease.

Deprenyl, an irreversible MAO-B inhibitor, is known to have a symptomatic effect in de novo patients with Parkinson's disease (PD). It has, however, not been studied thoroughly in patients with advanced PD and response fluctuations. This study evaluated the effect of washout of deprenyl in patients with long-standing PD. Eleven PD patients who were on chronic treatment with deprenyl (mean age 57 +/- 8 years, mean disease duration 8.4 +/- 2.9 years), seven with response fluctuations, were enrolled in a double-blind study of a novel MAO-B inhibitor. A deprenyl washout period of one month was required prior to initiation of treatment with the trial drug. Patients were evaluated by Unified Parkinson's Disease Rating scale (UPDRS) before and one month after the washout period. Motor function was quantified by computerized tapping speed and movement time test. Results showed that neither total UPDRS scores (22 +/- 16 vs. 18 +/- 16, respectively) nor tapping speed and movement time changed significantly (4.4 +/- 0.5 vs. 4.2 +/- 0.3 Hz and 159 +/- 45 vs. 161 +/- 40 seconds; p > 0.1, respectively). However, eight patients reported various degrees of subjective deterioration, among them were the seven fluctuating patients. Two patients first began to experience response fluctuations during the washout period. It seems that deprenyl has a symptomatic effect, especially in patients with response fluctuations, and it may postpone the appearance of fluctuations in patients with PD. Attempts to discontinue treatment with deprenyl may aggravate disease symptoms.

Abnormal skin wrinkling in the less affected side in hemiparkinsonism-a possible test for sympathetic dysfunction in Parkinson's disease.

Some patients with Parkinson's disease (PD) suffer from autonomic dysfunction, even in the early stage of the disease. We examined the skin wrinkling response following immersion of the hands in warm water in 18 patients with hemiparkinsonism. This test evaluates the function of the sympathetic autonomic system. Mean age of the patients was 61 +/- 10 and mean disease duration 5.5 +/- 3.5 years. Both hands of each patient were immersed in warm water for 30 minutes and the number of skin ridges of the fingertip of each finger was counted. The results of each hand were compared to those of nine healthy controls. The mean number of the ridges of the less affected hand was significantly decreased as compared to the affected hand and controls (6.1 +/- 6.8 vs 13.1 +/- 6.8 and 15.3 +/- 8.5, respectively; P < 0.01). These results suggest that autonomic dysfunction is prevalent in the less affected side of patients with PD and can be simply tested by the skin response test.

New therapies for Parkinson's disease.

In the last decade there has been a surge of new therapeutic strategies for the treatment of Parkinson's disease along with a change of concepts about how the disease should be treated. The gold standard remains levodopa preparations, which have a rapid and dramatic symptomatic effect by replenishing the reduced dopamine levels in caudate and putamen nuclei. However, keeping in mind the complications that may emerge following long-term treatment, its initiation should possibly be delayed to the more advanced stages of the illness, especially in younger patients, in favour of dopamine agonists monotherapy. The adverse reactions that become prominent and disabling in late stages of the disease, i. e., dyskinesias, response fluctuations, and psychiatric side effects, can currently be managed by novel pharmacological as well as surgical strategies. Future therapies will focus on transplantation of dopaminergic embryonic tissue, gene therapy, and neuroprotective treatments.

The pharmacokinetic profile of the "first ever" oral dose of levodopa in de novo patients with Parkinson's disease.

To understand the delay in the clinical benefit that commonly occurs after initiation of levodopa (L-Dopa) treatment, we examined the pharmacokinetic profile of L-Dopa after the first oral dose ever taken of L-Dopa/carbidopa in untreated patients with Parkinson's disease and followed these parameters after 1 month of treatment. This was performed in correlation with the clinical therapeutic effect. Plasma levels of L-Dopa were measured with use of high-performance liquid chromatography with electrochemical detection after administration of the "first ever" 125 mg L-Dopa/12.5 mg carbidopa tablet in 15 patients with de novo Parkinson's disease (mean age, 69 +/- 11 y, mean disease duration, 1.5 +/- 0.8 years). Blood samples were drawn before administration and thereafter at various intervals for a period of 4 hours. Repeated measurements after the same oral dose were performed after 1 month of continued therapy with L-Dopa/carbidopa 125/12.5 mg three times daily. Patients were clinically evaluated by unified Parkinson's disease rating scale motor scores. There was a modest clinical improvement after 1 month of continuous L-Dopa treatment (motor scores, 13.1 +/- 11.6 vs. 17.6 +/- 11.7; p < 0.01). Peak plasma L-Dopa levels and area under the curve did not differ significantly between the first-ever dose and after 1 month of continuous treatment (0.9 +/- 0.1 vs. 1.0 +/- 0.1 microg/mL and 66.0 +/- 30.9 vs. 86.2 +/- 34.9 microg/mL, respectively; p < 0.1. There was also no change in time to peak levels between measurements. Results indicate that the first-ever dose of oral L-Dopa is well absorbed and that pharmacokinetic mechanisms such as reduced absorption of L-Dopa probably do not play a major role in the initial delay in clinical response to oral L-Dopa/carbidopa in patients with Parkinson's disease. The latter phenomena may be linked to central pharmacodynamic mechanisms.